The goal of the proposed research is to design a multi-component HIV-1 vaccine with a rationally-designed envelope (Env) antigen that can induce durable protective immunity against homologous and heterologous virus challenges in the SHIV/rhesus macaque model. Three antigenic components, Env, Gag, and Pol, will be utilized to induce an array of effector mechanisms to facilitate the most broadly protective responses. These antigens have been chosen to cover the spectrum of targets that may be desirable in an effective vaccine: Env, for protective antibody responses; Gag and Pol for protective cellular responses against a conserved viral antigen. The expression, formulation, and delivery of these antigens will be pursued by state-of4he art approaches. Vaccines will be delivered as adjuvanted (ISCOMS) or formulated proteins (on microparticles) or peptides (for Env antigens) or as DNA vaccines delivered adsorbed to polylactide coglycolide (PLG) microparticles or by electroporation, or as combinations thereof. Both parenteral and mucosal routes of vaccine administration will be tested. The program comprises 2 projects and 2 scientific cores. Both projects will focus on the design, production, and formulation of novel HIV Env immunogens for the induction of broadly reactive neutralizing antibodies that will then be supplemented with Gag and Pol antigens. Env antigen designs will be based on current structural information regarding HIV-1 envelope glycoprotein and its interactions with host cell receptors during virus binding, entry, and fusion. Project 1 will focus on novel immunogens that are structurally modified to expose important conserved epitopes through deletions of variable (V)-regions and "bridging-sheet" structures in the Env surface glycoprotein; this project will also evaluate Env proteins complexed to CD4 miniproteins. Project 2 will evaluate multivalent and primeboost strategies using ISCOM formulated proteins and conserved mimotope and/or peptide boosts. Both subtype B and non-subtype B HIV-1 envelopes will be studied. The scientific cores will be: the Vaccine Technologies Core (Core B) and the Primate Models/Virology and Immunology Core (Core C). This program structure should provide for the performance of well-controlled comparative evaluations in primates of the proposed vaccines. These efforts are expected to lead to the selection of a strong candidate vaccine regimen for future clinical evaluations.